In patients with ischemic heart disease, regions of the heart may be poorly perfused, dysfunctional, but still viable. Myocardial ischemia limits blood flow and therefore the available supply of oxygen. This limited availability of oxygen affects oxidative metabolism, which ultimately negatively affects the production of adenosine triphosphate (ATP), essential for maintenance of contractility and cellular integrity. Varied states of ischemia exist. However, either transient or chronic ischemia may result in partial reduction of myocardial ATP with subsequent impairment of contractile function, but not cell death.
Various diagnostic methods have been developed to aid in determining whether areas of myocardium are xe2x80x9chibernating,xe2x80x9d xe2x80x9cstunned,xe2x80x9d or are non-viable. Hibernating myocardium is generally considered to be myocardium that has modulated its function and therefore energy requirements in response to chronic poor perfusion. Stunned myocardium denotes an acute, transient episode of poor perfusion due to coronary vasospasm, coronary artery disease or other maladies. This determination of viable, though poorly functioning mycardium, versus non-viable myocardium is essential to first, identify and second, to predict eventual clinical outcome following a revascular intervention. One newly developed therapy where, the distinguishing of viable versus non-viable myocardium is crucial for an optimal outcome, is the partial left ventriculectomy or remodeling procedure of Batista (R. Batista, Eur. J. Cardiothoracic Surg., (1999) Suppl. 1, pp. 512. See particularly the discussion on pp. 539-43.)
End stage heart disease is often treated by transplantation of a healthy donor heart. Approximately 2500 patients were listed and waiting for heart transplant in the United States in 1996, with an additional 300 new listings each month. The availability of donor hearts is limited and typically, about 20% of those on the list die before a suitable heart is available. (Jessup, Mariell: Cardiol. Rev. (1996) 4:5, 286-191.) The usual criteria for selection to this waiting list covers a wide spectrum of patients, from those in extremely critical condition, close to death, to others who could be well sustained on aggressive drug therapy for a time period, with potential improvement in cardiac status, if a more accurate assessment of vitality were possible. Clearly, the recipient evaluation process would benefit from the application of objective, quantifiable criteria needed for estimating either success of transplant or the determinants of survival without transplant.
Many techniques have been developed to measure blood flow and cardiac function in the various segments of the heart. Bax et al. published a review of currently available techniques, which include positron emission tomography with fluorine-18 fluorodeoxyglucose, thallium (T1)-201 stress- redistribution-reinjection, T1-201 rest-distribution, single photon emission tomography with technetium-99 m and low dose dobutamine echocardiography. (Bax et al J. Am. Coll. Cardiol. (1997) 30:1451-1460.)
Positron emission tomography (PET) scans have been considered to be the gold standard as a tool of diagnostic cardiology, however, newer computer-based techniques for acquisition and display of echocardiograms have generated increasing interest in the method for assessing the condition of the myocardium (Sawada et al. (1991) Circulation, 83: 1605-1614.) Measurement of ventricular wall thickness, segmental wall movement, ejection fraction and volume have been correlated with myocardial function. During echocardiography, a radar signal is sent through an esophageal or transthoracic probe, into the chest, and picked up by a monitor. A dobutamine infusion uncovers areas of reduced perfusion that were not apparent prior to using dobutamine. Studies have shown that segmental wall motion abnormalities can correlate with the distribution of at least one significantly diseased vessel in 93% of the patients with multivessel or main vessel disease.
The need remains for an improved method for distinguishing viable from non-viable myocardium as a diagnostic tool and for decision-making in subsequent therapy.
It has been investigated and is here disclosed that the beneficial effects of D-ribose on ATP levels, in the presence of a vasodilator and/or inotropic agent, improves the identification of viable versus non-viable myocardium in patients with cardiovascular disease. The effect of D-Ribose on wall motion seen on echocardiography examination was studied in various populations suspected of having stunned or hibernating myocardium.
This invention provides an improved method to diagnose viability of myocardial segments which have the potential for functional recovery after revascularization. This invention further provides D-Ribose alone or preferably in combination with vasodilators and/or inotropic agents to increase the sensitivity of detection of viable, stunned or hibernating tissue.
Myocardial hibernation and stunning define conditions in which tissue viability may be present but is hindered in the presence of reduced regional or global blood flow. The phenomenon of hibernating and stunned myocardium has been the subject of increasing interest with recognition that function may improve in these regions after restoration of adequate blood supply or treatment with newly available therapies such as the Batista procedure, in which the diastolic volume of the ventricle is surgically reduced by removal of non-viable or poorly viable tissue. The resulting ejection efficiency of the ventricle is improved with the patient usually experiencing a clinical benefit.
Among the techniques used to distinguish non-viable from viable myocardium, echocardiography is commonly used because of its direct measurement of contractile function, which is thought to be a better predictive indicium than blood-flow tracing with radionuclides. However, the sensitivity of this method, as with other methods such as thallium imaging and PET scan, may be limited in the presence of severe coronary artery disease (CAD). It has been previously found that the use of low dose dobutamine enhances the diagnosis of viable myocardium (Sawada et al, 1991). It has also been previously found that D-Ribose improves thallium imaging. (Angello et al, (1989) Am. J. Ar. Imag. 3:256-265.) It has now been discovered that the diagnosis is further enhanced by the combination of a vasodilator, inotropic agent and D-Ribose, leading to a more optimal clinical outcome.
Coronary artery bypass grafting (CABG) has become a routine procedure. During this procedure, blood flow is restored to regions of the heart served by stenotic coronary arteries. Identification of those areas that are hibernating or stunned rather than non-viable aids the surgeon in revascularizing those regions that are most capable of being revived and improved with reperfusion.
Once viability has been determined, various methods of revascularization may be considered by the medical personnel and offered to the patient. Ischemia may be viewed in the disease state as either acute or chronic, and decisions made according to the following Table:
Each treatment carries its own risks and benefits. For example, angioplasty has a lower rate of long-term success than CABG due to the tendency of the vessel to reocclude ( xe2x80x9crestenosisxe2x80x9d), but because it is a simpler procedure with lower risks, it will be often indicated as a first course of action, when the patient has an amenable lesion. However, not all patients carry the same preoperative risk for each procedure. If the heart contains large areas of non-viable tissue with severely decreased myocardial performance, a heart transplant rather than CABG may be the patient""s only alternative.
The references identified in the specification are incorporated herein by reference to the extent that they supplement, explain, provide background for, or teach the methodology, techniques and/or compositions employed herein.
The following examples are included to demonstrate preferred embodiments of the invention. In each example, D-Ribose is disclosed as the preferred embodiment. However, it is known in the art that certain pentoses such as xylitol and ribulose are readily converted to D-Ribose in vivo. Therefore, the term xe2x80x9cD-Ribosexe2x80x9d is intended to include such precursors of D-Ribose. D-Ribose is readily absorbed from the intestinal mucosal or from the peritoneum, and can therefore be administered orally, by intravenous infusion or by peritoneal infusion. Likewise, the examples use dobutamine as a vasodilator/inotropic agent. Dobutamnine in the agent of choice because it has a dual effect on the myocardium, acting both to dilate the coronary arteries and as an inotrop to increase the contractility of the myocardium. Dobutamine can readily be replaced by similar compounds such as arbutamine or isoproterenol. However, those of skill in the art can readily appreciate that a combination of vasodilators and inotrops will produce an equivalent effect. Such vasodilators that can be used are listed as Group I: dobutamine, arbutamine, nitroglycerine, nitrates, nitrites, papaverine, isoproterenol, nylidrin, isoxsuprine, L-arginine, nitroprusside, adenosine, xanthines, ethyl alcohol, dipyramide, hydralazine, minoxidil, diazoxide and analogs of the foregoing. In addition, endogenous vasodilators such as nitric oxide and prostaglandins can be induced. Inotropic agents are listed as Group II: dobutamine, arbutamine, dopamine, amrinone, milrinone, and analogs of the foregoing. This invention therefore includes the use of D-Ribose or its equivalents plus dobutamine or its equivalents, including those equivalents formed by a combination of an agent chosen from each of Group I and Group II.
It should be appreciated by those skilled in the art that the techniques and dosages disclosed in the examples that follow represent techniques and dosages discovered by the inventors to function well in the practice of this invention, and thus can be considered to constitute preferred modes for its practice. However, those skilled in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments that are disclosed and still obtain a like or similar result without departing from the concept and scope of the invention. More specifically, it will be apparent that certain agents that are both chemically and physiologically related may be substituted for the agents described herein while the same or similar results would be achieved. All such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the spirit, scope and concept of the invention as defined by the appended claims.